Manoalide has been described in a variety of publications: ##STR2## [see, for example, Glaser KB, et al., Molecular Pharmacology, 36:782-8 (1989)] as a phospholipase A.sub.2 inhibitor. It differs from the compounds of the instant invention by containing a double bond in the furanone ring, by possessing a second, oxygen-containing ring in the side chain, and in the position of substitution of the side chain. It also has a highly complex, isoprenoid-type side chain.
U.S. Pat. No. 4,952,605 discloses several manoalide derivatives: manoalide diol (I), manoalide delta-lactone (II), manoalide delta-lactone acetate (III), dehydro-seco-manoalide (IV), luffariellolide (V), luffariellin A (VI), and luffariellin B (VII): ##STR3## as phospholipase A.sub.2 inhibitors. All of these compounds differ from those of the instant invention in ways similar to those listed for manoalide.
In Deems R. A., et al. [Biochim Biophys Acta 917:258 (1987)] is disclosed HDBD: ##STR4## also a PLA.sub.2 inhibitor. It differs from the compounds of the instant invention in the position of attachment of the side chain, by the appearance of two double bonds in the side chain, and by the presence of a double bond within the ring.
Kernan M. R., et al. [Experimentia 45:399 (1989)], is disclosed luffolide: ##STR5## as a PLA.sub.2 inhibitor. It resembles manoalide but has an even more complicated and rigid side chain.
U.S. Pat. No. 4,874,782 discloses compounds of the following general structure as phospholipase A.sub.2 inhibitors: ##STR6## where R is a C.sub.8 -C.sub.24 straight branched hydrocarbyl group optionally containing a total of 1-6 double and/or triple bonds and optionally containing an aldehyde or hydroxymethyl group, or R.sup.1 -L where L is a C.sub.2 -C.sub.12 straight or branched hydrocarbyl linking group optionally containing 1 or 2 double or triple bonds and R.sup.1 is naphthalenyloxy or benzylphenoxy. They differ from the compounds of the instant invention in the position of attachment of the side chain and in possessing a double bond within the furanone ring.
In European Patent Application 295,056 is given the general structure: ##STR7## where R.sup.1 is hydrogen or acyl; R.sub.4 is hydrogen, bromo, or chloro; Z is --CO-- or --C(OR.sub.2)H--; and R.sub.3 is with the proviso that R.sub.4 may not be bromo or chloro when R.sub.3 contains a double bond. The broken line can represent a single or double bond, although the only compounds exemplified contain a double bond.
They differ from the compounds of the instant invention in the requirement for oxygen in the side chain, by the presence (for the exemplified compounds) of a double bond in the furanone ring, and in the failure to appreciate that maximum inhibitory activity resides in a particular side chain length.
European Patent Application 369,811 discloses compounds of the following general structure as phospholipase A.sub.2 inhibitors: ##STR8## in which R is hydrogen or an acid-derived species, R.sub.1 is halogen, or substituted nitrogen, oxygen, or sulfur, and R.sub.2 is an alkyl group or derivative. They differ from the compounds of the instant invention in the position of attachment of the side chain to the furanone ring, in the requirement for a heteroatom in the side chain, and in the presence of a double bond in the furanone ring.
U.S. Pat. No. 4,957,917 discloses compounds of the following general structure as phospholipase A.sub.2 inhibitors: ##STR9## in which A is --CH(OCOR.sub.1)CH.sub.2 CO--Y, --CH.dbd.C(R.sub.2)--R (R.sub.2 is halogen or COR.sub.5), --CH.dbd.CH--CO--Z, --CH.dbd.C(R.sub.3)--CO.sub.2 R, C.tbd.C--R.sub.4 (R.sub.4 --alkyl), --CH.dbd.CH(CH.sub.2).sub.n OX, or --CH(Ph)CH.sub.2 CO--Y. They differ from the compounds of the instant invention in the position of attachment of the side chain, in the presence of an oxygen atom or unsaturation in the side chain, and in the occurrence of a double bond in the furanone ring.
Finally, Campbell M. M., et al. [Tetrahedron 14:4551-6 (1959)] disclosed compounds of the following general structure as PLA.sub.2 inhibitors: ##STR10## where R=propyl or arachidonoyl. They differ from the compounds of the instant invention in that they lack the 5-hydroxy group on the furanone ring, they have an aminoethylphosphate group attached at the 4-position, and they have a carbonyl group in the first position of the 3-substituent.
Phospholipase A.sub.2 activity results in the liberation of fatty acids, primarily arachidonic acid, by the hydrolysis of the sn-2 position of cellular phospholipids. Both the free arachidonic acid and the lysophospholipid thus resulting can be converted by other enzymes into potent inflammatory mediators. The acid can be converted into prostanoids, leukotrienes, lipoxins, etc., while the lysophospholipid can be converted into platelet activating factor (PAF). Elevated levels of phospholipase A.sub.2 have been demonstrated in several inflammatory conditions. For further discussion, a number of reviews have appeared. See for example, Mobilio D. and Marshall L. A. [Annual Reports in Medicinal Chemistry, Vol. 24, pg. 157 (1989)], Vadas P. and Pruzanski W. [Laboratory Investigation, Vol. 55:391 1986)], Hoffman G. E. and Guder W. [Klinische Woechenschrifte, Vol 67:149 (1989)], and Mansbach C. [Gastroenterology, Vol 98:1369 (1990)]. Inhibition of phospholipase A.sub.2 is thus an attractive approach to the control of inflammation.